The introduction of combination antiretroviral therapy (ART) has had major impact on morbidity and mortality of HIV-1 infected persons. Nonetheless, despite effective control of HIV replication with ART, a minority of treated persons fails to increase CD4+T cell counts to levels observed in uninfected subjects 1,2. These immune failure or immune non-responder (INR) subjects remain at greater risk for morbidity and mortality than are immune responders (IR) in whom CD4+T cell count is restored 3,4. Despite low CD4+T cell numbers, increased frequency of cycling CD4+T- cells is a hallmark of poor immune reconstitution in these persons1,2. In addition, high levels of inflammation are characteristic 1,5,6 and an exhaustion/senescence phenotype of CD4+T cells has been reported 5,6. Importantly, the INR phenotype is more common in older individuals 7,8. Based on our preliminary data, we hypothesize that mitochondrial dysfunction underlies the INR phenotype. We proposed a model where INR subjects fail to restore CD4+T cells as a consequence of defective mitochondrial fitness that affects negatively Treg survival and function. This leads to uncontrolled cell cycling, immune exhaustion, and increased cell death. The working hypothesis of this proposal in based on our preliminary data that will appear soon in the Journal of Clinical Investigation (Ref. 37). First, we showed that in all persons, cycling CD4+T cells are enriched for cells having a phenotype of regulatory T cells (Tregs). Second, sorted cycling CD4+T cells of INRs do not complete cell cycle or proliferate in vitro in contrast to findings among IR or healthy controls that do. Third, we found cycling Tregs of INR were dysfunctional by transcriptomic and flow cytometry analyses and this was linked to low CD4+T cell counts and to impaired mitochondrial activity. Fourth, we showed that exposure of cycling CD4+T cells and Tregs from INR to IL-15 corrects mitochondrial dysfunction and improves T cell proliferation by induction of the master regulator of mitochondrial biogenesis, the peroxisome proliferator- activated receptor gamma coactivator 1-alpha (PGC1?). Thus, we hypothesize that enhancing mitochondrial biogenesis might correct exhaustion and senescence that are characteristics of CD4+ T cells in INRs. PGC1? can be induced through at least three distinct pathways: 1) activation of the peroxisome proliferator-activated receptors (PPAR?, PPAR?, PPAR?) nuclear transcription factors regulating genes implicated in mitochondrial biogenesis and bioenergy9,10, 2) activation of AMP-activated protein kinase (AMPK) by agents such as Resveratrol and the AMP analog, 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR ) or 3) activation of the mammalian target of rapamycin (mTOR) (See Figure 2). We hypothesize that mitochondrial dysfunction drives immune failure in INRs as a consequence of diminished PGC1? expression that is correctible through exposure to IL-15 and/or combinations of PGC1? inducers (PPAR/AMPK/IL-15).